NM_001387283.1:c.4034C>T

Variant names:

• chr19-11034996-C-T
• rs746533073
• NM_001387283.1:c.4034C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001387283.1(SMARCA4):​c.4034C>T​(p.Ser1345Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39252377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4034C>T	p.Ser1345Leu	missense_variant	Exon 29 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4034C>T	p.Ser1345Leu	missense_variant	Exon 29 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4034C>T	p.Ser1345Leu	missense_variant	Exon 29 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4034C>T	p.Ser1345Leu	missense_variant	Exon 29 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3935C>T	p.Ser1312Leu	missense_variant	Exon 28 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3935C>T	p.Ser1312Leu	missense_variant	Exon 29 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3935C>T	p.Ser1312Leu	missense_variant	Exon 28 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3935C>T	p.Ser1312Leu	missense_variant	Exon 28 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3935C>T	p.Ser1312Leu	missense_variant	Exon 29 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3446C>T	p.Ser1149Leu	missense_variant	Exon 26 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2678C>T	p.Ser893Leu	missense_variant	Exon 22 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2660C>T	p.Ser887Leu	missense_variant	Exon 21 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2519C>T	p.Ser840Leu	missense_variant	Exon 21 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2387C>T	p.Ser796Leu	missense_variant	Exon 20 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.191C>T	p.Ser64Leu	missense_variant	Exon 3 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458144 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Jan 31, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with leucine at codon 1345 of the SMARCA4 protein (p.Ser1345Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.033
Eigen_PC	Benign	0.0092
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.024	D;.;.;.;.;.;.;.;.;.;D;.;D;.;T;.;.;.;.;.;.;.
Sift4G	Uncertain	0.053	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.49	P;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;P;.;.;.;.
Vest4		0.28
MutPred		0.33		Loss of phosphorylation at S1345 (P = 0.0189);.;Loss of phosphorylation at S1345 (P = 0.0189);.;.;.;.;.;.;.;Loss of phosphorylation at S1345 (P = 0.0189);.;.;.;.;.;.;Loss of phosphorylation at S1345 (P = 0.0189);.;.;.;.;
MVP		0.57
MPC		1.5
ClinPred		0.95	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.24
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746533073; hg19: chr19-11145672; COSMIC: COSV60809307; COSMIC: COSV60809307;